Abstract

Infants, including newborn babies, experience pain similarly and probably more intensely than older children and adults. They
are also at risk of adverse long term effects on behaviour and development, through inadequate attention towards pain relief
in early life. However, the issue of analgesia in young babies has been largely neglected in most clinical settings, despite
subjecting them to painful diagnostic and therapeutic procedures. Several therapeutic and preventive strategies, including
systemic and local pharmacological and non-pharamacological interventions, are reported to be effective in relieving pain
in infants. A judicious application of these interventions, backed by awareness and sensitivity to pain perception, on the
part of the caregivers is likely to yield the best results. This article is a review of the mechanisms of pain perception,
objective assessment, and management strategies of pain in infants.

Pain is defined as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage”.1 Obviously, this definition may not be easily applicable in day to day situations, particularly in infants whose responses
to pain are not very different from their response to fear and distress due to non-painful conditions. Therefore, it may be
worthwhile to widen the scope of the definition of pain to include pain related distress as well. Owing to a variety of reasons,
emphasis on the assessment and management of pain in this age group is lacking. Some of the possible reasons are highlighted
in box 1.

Box 1:
Possible reasons for the neglect of pain relief in infant management

PERCEPTION OF PAIN IN INFANTS

Infants perceive pain in the same way as adults. The receptors of nociceptive stimuli are free nerve endings that are widely
distributed all over the body. They are maximally present in the superficial layers of the skin and internal tissues such
as periosteum, arterial walls, and joint surfaces. Mechanical, chemical, or thermal stimuli excite the nociceptors and electrical
impulses are transmitted to the dorsal horn of the spinal cord through two sets of nerve fibres—namely, large myelinated A-delta
(A-δ) fibres and slower conducting, non-myelinated C fibres. The spinothalamic pathway transmits the impulses to the thalamus
where pain is perceived. Third order neurons terminating in the sensory cortex and basal areas of the brain probably influence
the appreciation of the quality of pain and the affective component. The neuronal pathways are modulated by neurotransmitters
that amplify or attenuate transmission. Similarly, affective and emotional components of the painful stimulus are modulated
through past experience and memory.

The periaqueductal grey and periventricular mesencephalic regions serve as an inherent analgesia system. Signals from these
regions are transmitted through nuclei in the pons and medulla, to the dorsal horn of the spinal cord, to block the sensation
of pain. The neurotransmitters involved in the suppression of pain are endogenous opiates that include β-endorphin, met and
leu encephalins, and dynorphin. Other neurotransmitters such as serotonin and gamma-amino butyric acid (GABA) also decrease
the sensation of pain. Figure 1 summarises the mechanisms of pain perception and suppression in the human body.

The anatomical, physiological, and biochemical prerequisites for pain perception are present by the early part of intrauterine
life. Therefore, even preterm infants can perceive pain comparable to older children.2,3 In addition, newborn babies have a well developed endocrine system that is able to release cortisol and catecholamines in
response to painful stresses,4 resulting in biochemical and physiological alterations that make it possible to objectively assess response to pain. Nevertheless,
there are some basic differences in the neurophysiology of pain perception in infants. Nociceptive impulses in babies travel
to the spinal cord through unmyelinated rather than myelinated fibres, and there is also a relative paucity of inhibitory
neurotransmitters in them.5 Babies also have larger receptive fields and possibly a higher concentration of substance P receptors.6,7 They have a lower threshold for excitation and sensitisation, resulting in more central effects of nociceptive stimuli.8,9 These factors are believed to make infants feel pain more severely than older persons.

ASSESSMENT OF PAIN

Although self reporting of pain is the gold standard for assessment of the site, nature, and severity of pain, it is not precisely
applicable in children below 3 years of age. Hence in infants, surrogate markers are used. Pain is associated with physiological,
biochemical, behavioural, and psychological alterations that can be recorded and to some extent, quantified. These changes
are summarised in table 1. It is reported that there may be up to 20% increase in the measurable physiological parameters
in response to pain. Box 2 highlights a case study reflecting this aspect of pain response. These changes are secondary to
increased cortisol and catecholamine secretion, which sets up the classical fight or flight sequence in older children and
adults. It is relatively easy to measure alterations in most of the physiological parameters without invasive equipment. These
measurements coupled with certain consistent behavioural responses are very sensitive indicators of infant pain. Of the behavioural
changes, the facial expression of the baby is considered the most reliable and consistent indicator,15 with the least interobserver disagreement as well.16 Although the biochemical changes are perhaps the most sensitive quantifiable parameters, the need to use invasive methods
is a major drawback. Hence they are not routinely used for assessment of pain perception. There is some evidence that a combination
of physiological and behavioural changes provides a better estimate of infant pain.

Box 2:
Case study

An 18 month male baby with a diagnosis of Guillain-Barré syndrome was mechanically ventilated for neuromuscular paralysis
in the intensive care unit of a teaching hospital. Intubation was performed under cover of 0.01 mg/kg intravenous midazolam.
He was also being given bolus doses of 0.01 mg/kg morphine intravenously every six hours. Despite respiratory stabilisation
and normal arterial blood gas analysis, the baby had persistent tachycardia, borderline hypertension, excessive sweating,
and marked restlessness. These findings were interpreted as autonomic instability associated with the primary clinical condition.
Propranolol in the dose of 1 mg/kg every eight hours was started; the blood pressure showed a slight decline, but the other
features of sympathetic overactivity did not subside. On the advice of one of the authors, morphine bolus doses were replaced
by infusion of 0.01 mg/kg/hour, which led to resolution of the symptoms and the omission of propranolol. The case study highlights
the importance of:

Being sensitive to infants’ perception of pain.

Recognition of infants’ responses to pain, which may be misinterpreted.

In order to introduce objectivity in the assessment of infant pain, various pain scales have been designed and validated.
These are based either on physiological variations, behavioural changes, or a combination of both. A detailed description
of these scoring systems is beyond the scope of this article. Box 3 lists some of the commonly used systems. While all these
methods of pain assessment are exciting for accurate measurement in research settings, it must be emphasised that highly sensitive
techniques may not always be necessary for effective management of pain. The mainstays of appropriate management include the
physician’s awareness of infant pain, appreciation of situations wherein pain occurs, sensitivity to the need for controlling
pain, and a generous measure of common sense.

Although the physiological and behavioural responses are very sensitive indicators of pain, they have poor specificity; and
can occur with apprehension, stress related to disease, and discomfort. The responses may also be altered by the physiological
state of the baby immediately preceding the painful stimulus, such as the stage of wakefulness,17 duration since last feed, restraint techniques used, etc. Despite these pitfalls, assessment of behavioural and physiological
responses remains the most readily available, reliable, and feasible method of assessing pain in infants.

CLINICAL SETTINGS FOR PAIN IN NEONATES AND INFANTS

The clinical settings for pain in infants are extremely varied. They include painful disease conditions—both acute and chronic—as
well as diagnostic and therapeutic procedures performed for the treatment of these conditions. It must be emphasised that
procedures need not always be invasive in order to cause pain. Even simple actions such as removal of sticking tapes, limb
compression during restraint, postural changes during ventilation, and physiotherapy manoeuvres can be intensely painful.
Table 2 is a partial list of some of the situations wherein infants experience pain.

CONSEQUENCES OF PAIN

Pain is a dynamic experience that is often beneficial by warning of impending or actual injury, thereby preventing or restricting
tissue damage. However, barring this aspect, pain has only damaging effects in terms of metabolic and behavioural responses
induced by it. Box 4 lists some of the adverse effects on infant pain. In the long term, memory of painful experiences has
effects on subsequent pain perception and response. The classical studies that demonstrated differences in response to vaccination
among infants who underwent circumcision without anaesthesia and those who received anaesthesia, testify to this.19,20 It is believed that learning about pain starts with the first painful experience and it may have effects on subsequent pain
perception and response. There is also some evidence that neonatal pain experience may have far reaching effects even up to
the preschool age21,22 and beyond.23 Multiple influences, including infant factors as well as characteristics of the caregivers, together contribute to such events
in development.24

From the point of view of those caring for neonates and infants, pain has two important deleterious consequences. The first
is the mistrust and fear towards the caregiver, generated by failure to prevent or relieve pain. Secondly, inadequate analgesia
for initial procedures can decrease the effect of adequate analgesic doses in subsequent procedures.

MANAGEMENT

The management of infant pain rests primarily on the tripod of (a) awareness of infants’ capacity to perceive pain, (b) sensitivity
towards clinical situations wherein pain may be encountered, and (c) appropriate steps to prevent and treat pain. In this
context, it is interesting that even in tertiary care centres, there is a wide variation in strategies for pain management,
ranging from the absolute absence of use of pain assessment techniques25 to protocols wherein doses, regimens and routes of administration are not standardised.26 Box 5 reflects the basis of infant pain management.

Box 5:
Basis of management strategies for infant pain

Awareness of infants’ capacity to perceive pain.

Sensitivity to situations where infants may experience pain.

Prevention of pain.

Assessment of cause and severity of pain.

Pharmacological interventions.

Non-pharmacological interventions.

Modification of techniques used for diagnostic and therapeutic procedures.

Pharmacological interventions

Systemic administration of drugs

The opioids, including morphine, methadone, oxymorphine, codeine, fentanyl, alfentanil, and sufentanil are the most potent
class of analgesic drugs. They have the added advantage of a sedative and anxiolytic effect. Another relative advantage of
this group is that in the event of over dosage, the effects are easily reversed. However, these drugs have the potential for
tolerance and dependence, the long term effects of which have not been studied in babies.27 They also have a variable half life period that often depends on the gestational age; hence dose and frequency of administration
must be titrated against clinical effects. Although there is plenty of scientific evidence to support the use of opioid drugs
in infants, the risk of adverse effects, particularly of respiratory and central nervous system depression, often hampers
the rational use of these agents, especially in young babies. These effects can be reduced by modifying the route and method
of administration as well as meticulous monitoring.

Non-steroidal anti-inflammatory drugs (NSAIDs) are generally used to treat pain of lesser intensity and as an adjunct to reduce
the total dose of opioids.28 Only some of these drugs have been studied in young infants; however, they may be valuable in situations where pain relief
is required for a longer duration, and where the risks of inducing opioid dependence may be a significant problem. One of
the popular NSAIDs, nimesulide, has recently been banned for use in children due to potential hepatotoxic effects. Even a
brief description of the available analgesics is outside the scope of this article. From practical experience, it would be
rational to use a combination of analgesics with differing properties, to achieve the best results with the fewest side effects.

Before any analgesic or anaesthetic drug is systemically administered to infants, the pharmacokinetic and pharmacodymanic
properties of the drug must be studied. This is because most of these drugs are handled differently in babies compared with
adults. In addition, the clinical status of the baby with special reference to drug metabolising and excreting capacity must
be thoroughly understood. Young babies, especially those who are premature and of very low birth weight, have immature drug
handling capabilities that necessitate reduction in dosage or increasing the interval between doses. Another aspect that must
be looked into before administration of these agents is the type of medication the baby is already receiving for the clinical
condition, so that undesirable interactions do not occur.

Local techniques

Local anaesthetic agents block the transmission of impulses from receptors to the spinal cord. Theoretically speaking, they
can be administered in any one of three ways—infiltration into the local area, nerve blockade, or intravenous regional block.
The latter two methods demand a high degree of technical expertise and may not be feasible during routine diagnostic and therapeutic
procedures. The safety and efficacy of infiltration of local anaesthetic drugs have been well documented for short surgical
procedures such as circumcision and diagnostic procedures like bone marrow aspiration, biopsies, etc. Nevertheless, they are
not widely used, for two major reasons. The first is the real or supposed risk of side effects of local anaesthetic, which
includes anaphylaxis, hypotension, and other less serious effects. This is a risk that has to be taken into account. However,
the more common reason probably is the temptation on the part of the physician to perform a “quick in, quick out” procedure
and “spare” the baby the pain of two needle pricks. Such an attitude must be vigorously discouraged, particularly as the pain
of local anaesthetic infiltration can be substantially minimised or even obviated by using narrowest available needles for
infiltration, neutralising the pH of the local anaesthetic,20 warming the drug to body temperature before use, and injecting as slowly as possible. It is also recommended to infiltrate
the subcutaneous space before raising a wheal, as epidermal stretching is very painful.

The various local anaesthetic agents used are lignocaine, available as injectable, spray and gel preparations, bupivacaine,
amethocaine gel,21 and ropivacaine. Mixing the local anaesthetic with adrenaline increases the duration of action; however this must never be
used in regions supplied by end arteries such as the penis, fingers, and toes. Local anaesthetic agents are regarded as having
a relatively poor safety margin, and hence resuscitation equipment should be available before use.

A eutectic mixture of 2.5% lignocaine and 2.5% prilocaine, designated EMLA (eutectic mixture of local anaesthetics) is becoming
increasingly popular. The eutectic combination is a mixture of the two local anaesthetic drugs in a 1:1 weight ratio, whereby
the crystalline powders melt at a lower temperature than they do separately, hence they constitute a liquid at room temperature.
This combination increases the concentration of the drugs in the emulsion droplets and is more effective than using both drugs
together.22 Applied about 60 minutes before the intended procedure, it penetrates up to a depth of 5–10 mm, providing good anaesthesia
for several minutes. The penetration can be increased by applying occlusive dressings onto the smeared surface. However, EMLA
must not be used on abraded skin surfaces or mucus membranes. The major drawbacks of EMLA are vasoconstriction and risk of
methaemoglobinaemia. A mixture of tetracaine, amethocaine, and cocaine abbreviated as TAC, is another popular local anaesthetic
in some parts of the world.

Adjunctive drugs

These are drugs with little analgesic or anaesthetic effect, but useful as adjuncts with analgesics, by virtue of their sedative
and/or hypnotic properties. However, they are not replacements for analgesics. In fact, they can suppress some of the behavioural
responses associated with pain, thereby interfering with assessment and appropriate management. With appropriate monitoring
of heart rate, respiratory rate and transcutaneous oxygen saturation, these agents can be safely and efficaciously used to
advantage.

Non-pharmacological interventions

These are interventions that enhance activity in descending inhibitory systems and thereby decrease pain perception. Attenuation
of transmission of impulses to the spinal cord can be achieved by stimulation of large sensory nerve fibres mediating sensations
of touch and heat/cold. The non-pharmacological interventions may also modulate pain sensation and response to pain through
changes in attention and decreasing apprehension. Some of the strategies are listed in box 6. It must be re-emphasised that
non-pharmacological interventions practised in isolation are unlikely to relive pain. They are more useful as complementary
strategies to pharmacological methods of relieving acute pain.

Box 6:
Non-pharmacological interventions to relieve infant pain

Positioning and restraining the infant in a relatively flexed posture.29

The non-pharmacological interventions have the allure of being easy to administer and require no intensive monitoring. Although
there are no adverse effects reported with their use, a recently published double blind, randomised, controlled trial has
noted that the repeated use of sucrose analgesia in infants less than 31 weeks’ gestation may put them at risk for poorer
neurobehavioural development and physiological outcomes in later weeks of life.38

Modification of techniques

The basic principle behind modifying operational techniques is to reduce the incidence and frequency of stimuli that may be
perceived as noxious. This encompasses minimal handling of sick babies, avoiding sampling and painful procedures during sleep
cycles, not sticking adhesive tapes onto hair, moistening tapes before removal, reducing harsh noise and light in treatment
areas,13 and controlling thermal stress.

Often, a change in procedural practice may help in reducing pain of neonates and infants. For example, infants show significantly
fewer signs of pain during heel puncture with the use of mechanical lancets as opposed to manual lancets.39,40 Similarly, venous puncture for blood sampling is reportedly less painful than heel puncture.41 One may also consider insertion of central venous catheters in babies requiring frequent blood sampling or intravenous medications,
as against repeated venous and heel punctures. Naturally, such an option must be weighed in the light of expected duration
of cannulation and risks of infection and thrombosis. However, there are data showing that infection rate in centrally cannulated
babies is not higher than in those undergoing multiple punctures. In neonatal circumcisions, use of the Mogen clamp is preferred
to the Gomco clamp because it is associated with less pain.42

CHRONIC PAIN

There are certain conditions that result in pain over prolonged periods, either as repeated short episodes or as a continuous
phenomenon. A frequently encountered situation is the infant with a malignant condition. In such situations, the goals of
pain relief are to provide maximum comfort for prolonged periods of time. Hence analgesics and anaesthetic agents with a long
duration of action but few systemic side effects are desired. Butamben is a local anaesthetic agent that can produce sensory
blockade for several months when injected epidurally. Its added advantage is the sparing of motor neurones, though this aspect
is controversial at present. An alternate method of increasing the duration of anaesthetic activity may be to use slow release
preparations of local anaesthetic. There is some progress towards preparation of liposomes and sustained release microspheres
containing local anaesthetic. Another option may be to consider nerve plexus blockade43 or even ablation using alcohol or phenol; this is supposed to be effective for up to six months. The instillation of analgesics
through indwelling epidural catheters44 and the intrathecal route45 is also under consideration.

The World Health Organisation has suggested a protocol of a four step graded approach to pain management in cancer. This involves
starting with non-opioid analgesics, then using opioids orally, followed by parenteral use of potent opioids, and lastly more
invasive treatment such as intrathecal or epidural administration of drugs, nerve blockade, etc. It is the opinion of some
experts that such treatment is likely to be inferior to using a multipronged attack in the management of chronic pain.

PRE-EMPTIVE ANALGESIA—PREVENTION IS BETTER THAN CURE

The general tendency among those caring for young babies is to treat pain after it has occurred.46 However, prevention being better than cure, it is appropriate to administer appropriate dosages of analgesics with or without
sedatives whenever pain is anticipated in babies. Such an approach is not only more humane, reducing the distress of infants,
their parents and caregivers, but it also has the added benefit of making management of the child’s clinical condition as
well as diagnostic or therapeutic procedures easier to perform.

CONCLUSION—PAIN IN PERSPECTIVE

The physician caring for neonates and infants has to be sensitive to the fact that babies perceive pain as much as adults,
although their expression of this may be subject to misinterpretation. Pain experience in young babies may have far reaching
consequences not only in the short term, but in the long term as well. Appropriate assessment and management of pain is not
only good clinical practice, but is also necessary to prevent adverse effects in sick babies. There is a wide variety of therapeutic
approaches to choose from; and the ideal may be to use a combination strategy.47 It may also be worthwhile to develop institutional protocols for the specific purpose of pain management in infants.